It is known that the infection of human immunodeficiency virus is one of the most frequent highly dangerous infections having contaged 37.7 million adults and 2.2 million children in late 2004 BROCKLEHURST, P, et al. Antiretrovirals for Reducing the Risk of Mother-to-Child Transmission of HIV Infection. Cochrane Database Syst Rev. 2002, no. 2.
In HIV/AIDS treatment, Zidovudine (AZT), Stavudine and Lamivudine that inhibit polymerase-γ, a ferment responsible for HIV-1 mitochondrial deoxyribonucleic acid (mtDNA) replication, are most widely used. Thus, Zidovudine and Stavudine and Lamivudine block the formation of new mitochondria and cause other side effects.
Meldonium, chemically, 3-(2,2,2-Trimethylhydrazinium) propionate is disclosed in U.S. Pat. No. 4,481,218 (INST ORGANICHESKOGO SINTEZA AK (SU)) 8 Jul. 1982.
Meldonium is extensively applied in medicine as an anti-ischemic and stress-protective drug in treating various cardio-vascular diseases and other pathologies involving ischemia.
Zidovudine, chemically, 3′-Azido-3′-deoxythymidine; azidothymidine; or AZT is a reverse transcriptase inhibitor. The therapeutic uses of zidovudine and related compounds, and their preparations were disclosed in U.S. Pat. No. 4,724,232 (BURROUGHS WELLCOME CO (US)) 17 Sep. 1985.
Zidovudine is commercially available as 100 mg capsule, 300 mg tablet, 10 mg/mL in 20-mL single-use vial and 50 mg/5 mL in 240 mL syrup.
Lamivudine, chemically, (2R-cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(IH)-pyrimidinone; (−)-2′-deoxy-3′-thiacytidine; (−)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; or 3TC is a reverse transcriptase inhibitor. The therapeutic uses of lamivudine and related compounds and their preparations were disclosed in WO 9117159 (IAF BIOCHEM INT (CA)) 2 May 1991
Lamivudine is commercially available as 100 mg, 150 mg and 300 mg tablets; 10 mg/mL in 240 mL oral solution.
Stavudine, chemically, 2′,3′-Didehydro-3′-deoxythymidine; 1-(2,3-dideoxy-β-glycero-pent-2-enofuranosyl)thymine; or 3′-deoxy-2′-thymidinene is a reverse transcriptase inhibitor. The therapeutic uses of stavudine and related compounds and their preparations were disclosed in U.S. Pat. No. 5,130,421 (BRISTOL MYERS CO (US)) 29 Apr. 1991
Stavudine is commercially available as 15 mg, 20 mg, 30 mg and 40 mg capsules; and 1 mg/mL in 200 ml oral solution.
Several approaches are known how the adverse reactions caused by Zidovudine, Stavudine and Lamivudine toxicity may be restricted. Nevertheless, none has simultaneous effect on functioning of both cardiomyocytes and neurons.
For the purpose of diminishing mitochondrial damage, additional use of antioxidants, e.g. very high doses of Vitamin C and Vitamin E is recommended in particular cases BROCKLEHURST, P, et al. Antiretrovirals for Reducing the Risk of Mother-to-Child Transmission of HIV Infection. Cochrane Database Syst Rev., 2002, no. 2; FICHTENBAUM, C. J. Coronary Heart Disease Risk, Dyslipidemia, and Management in HIV-Infected Persons. HIV Clin Trials. 2004 November-December, vol. 5, no. 6, p. 416-433.
It is proved in trials on mice that daily doses of Vitamin C 1,250 mg/kg and daily doses of Vitamin E 75 mg/kg protect mitochondria against oxydative stress as well as reduce the activity of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and also confine the damage of mitochondrial ultrastructure. Creatine kinase (CK) activity similarly subsides which reinforces in case of zidovudine application PETERS, B. S., et al. Mitochondrial Myopathy Associated with Chronic Zidovudine Therapy in AIDS. Q J Med. 1993 January, vol. 86, no. 1, p. 5-15.
Coenzyme Q10 may be regarded as another substance capable of exerting a positive influence in preclusion of zidovudine adverse reactions by activating electron transfer in the respiration chain; riboflavin, tocopherol, succinates, ascorbinic acid, Menadione, and nicotinamide putatively inhibit the respiration chain blockage LARSSON, N. G., et al. Mitochondrial Myopathies. Acta Physiol Scand. 2001, no. 171, p. 225-233.
WO 9705864 (SIGMA TAU IND FARMACEUTI (IT); MENDES SRL (IT); MORETTI SONIA (IT)) 19 Jul. 1996 provides information concerning a novel use of L-carnitine, the derivatives thereof and their pharmacologically acceptable salts in combination with antiretroviral drugs for reducing ceramide levels, enhancing the activity of the aforesaid antiretroviral drugs for the therapeutic treatment of HIV-infection and AIDS and enhancing the immune system affected by these drugs.
In EP 0560275 A (SIGMA TAU IND FARMACEUTI (IT)) 9 Mar. 1993 were disclosed a novel therapeutic utilization of L-carnitine and the pharmacologically acceptable salts thereof for treating carnitine-depleted HIV-seropositive patients.